The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning
The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning
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DOI：
10.1101/412783
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发表时间：
2018-09
影响因子：
14.9
通讯作者：
A. Swanston;Katerina Zabrady;Helder C. Ferreira
中科院分区：
文献类型：
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作者：
A. Swanston;Katerina Zabrady;Helder C. Ferreira
拓扑异构酶II（Top2）是通过瞬时Top2-DNA共价中间体使DNA脱链的必需酶。这种中间体可以被一类称为Top2毒药的药物稳定，导致大量的DNA损伤。因此，Top2活性是一把双刃剑，需要仔细控制以维持基因组稳定性。我们表明，Uls1，ATP依赖的染色质重塑（Snf2）酶，可以改变Top2染色质结合，防止Top2中毒酵母。ULS1的缺失突变体对Top2毒物吖啶黄（ACF）高度敏感，激活DNA损伤检查点。我们绘制了Uls1的Top2相互作用结构域，并表明这与其ATP酶活性一起对Uls1功能至关重要。通过执行ChIP-seq，我们表明ACF导致整个基因组中Top2结合的普遍增加。我们映射Uls1结合位点，并确定tRNA基因作为关键区域，Uls1协会后ACF处理。重要的是，Uls1在这些位点的存在阻止了ACF依赖性Top2的积累。我们的数据揭示了Top2毒物对全球Top2结合景观的影响，并强调了Uls1在拮抗Top2功能中的作用。因此，重塑Top2结合是Snf2酶促进基因组稳定性的重要新手段。
Topoisomerase II (Top2) is an essential enzyme that decatenates DNA via a transient Top2-DNA covalent intermediate. This intermediate can be stabilised by a class of drugs termed Top2 poisons, resulting in massive DNA damage. Thus, Top2 activity is a double-edged sword that needs to be carefully controlled to maintain genome stability. We show that Uls1, an ATP-dependent chromatin remodelling (Snf2) enzyme, can alter Top2 chromatin binding and prevent Top2 poisoning in yeast. Deletion mutants of ULS1 are hypersensitive to the Top2 poison acriflavine (ACF), activating the DNA damage checkpoint. We map Uls1’s Top2 interaction domain and show that this, together with its ATPase activity, is essential for Uls1 function. By performing ChIP-seq, we show that ACF leads to a general increase in Top2 binding across the genome. We map Uls1 binding sites and identify tRNA genes as key regions where Uls1 associates after ACF treatment. Importantly, the presence of Uls1 at these sites prevents ACF-dependent Top2 accumulation. Our data reveal the effect of Top2 poisons on the global Top2 binding landscape and highlights the role of Uls1 in antagonising Top2 function. Remodelling Top2 binding is thus an important new means by which Snf2 enzymes promote genome stability.